Download Phytochemicals and functional foods. Current situation

Phytochemicals and functional foods, Rodriguez et al.
Phytochemicals and functional foods. Current situation and
prospect for developing countries
Evelyn B. Rodriguez1, Maxima E. Flavier1, Delia B. Rodriguez-Amaya2 and Jaime Amaya-Farfán2
This review updates and attempts to present the complex panorama of bioactive phytochemicals and functional
foods. For such purpose and given the breadth of the field, it was necessary to survey a large volume of scientific
literature. The different types of studies used to provide evidence for efficacy are described. The different groups
of health-promoting substances (carotenoids, phenolic compounds, phytosterols and phytostanols, tocotrienols,
organosulfur compounds, nondigestible carbohydrates) are presented with a discussion of the dietary sources
and the chemical and biological properties that explain their modes of action. Functional foods of plant origin
(broccoli and other cruciferous vegetables, oat, flaxseed, tomato, soybean, citrus, berries, tea, grapes and wine,
garlic) are discussed in terms of their health effects, the phytochemicals responsible and the body of evidence
supporting such effects. The review emphasizes the importance of consuming fruits and vegetables for the
general state of health of the population and points out some technical and scientific opportunities that can be
explored in developing countries.
Keywords: functional foods, phytochemicals, fruits and vegetables, health promotion, healthy eating, degenerative
diseases
Substâncias fitoquímicas e alimentos funcionais. Situação atual a
perspectivas para países emergentes.
Esta revisão atualiza e tenta apresentar o panorama complexo de fitoquímicos bioativos e alimentos funcionais. Neste contexto e considerando a amplitude do assunto, foi necessário relacionar um vasto volume de
literatura científica. São descritos os diferentes tipos de estudos utilizados para obter evidência de eficácia.
Os diferentes grupos de substâncias que promovem saúde (carotenóides, compostos fenólicos, fitoesteróis e
fitoestanóis, tocotrienóis, compostos organosulfurados, carboidratos não digeríveis) estão apresentados com
uma discussão das fontes alimentícias e das propriedades químicas e biológicas que explicam os seus modos
de ação. Alimentos funcionais de origem vegetal (brócoli e crucíferas, aveia, linhaça, tomate, soja, citrus, amoras, chá, uva e vinho, alho) estão discutidos em termos dos seus efeitos na saúde, dos fitoquímicos responsáveis e o conjunto de evidências que apóia tais efeitos. A revisão enfatiza a importância de consumir frutas e
hortaliças para o estado geral de saúde da população e aponta oportunidades técnicas e científicas que podem
ser exploradas nos países em desenvolvimento.
Palavras-chave: alimentos funcionais, fitoquímicos, frutas, hortaliças, alimentação saudável, promoção da saúde, doenças
degenerativas.
Institute of Chemistry, University of the Philippines at Los Baños, College, Laguna 4031, Philippines
Faculty of Food Engineering and Center for Food Security Studies - NEPA, State University of Campinas, C.P. 6121, 13083-862 Campinas, SP,
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Phytochemicals and functional foods, Rodriguez et al.
Introduction
The new concept of functional foods raises
concerns about food security and the proper selection
of an adequate diet, beyond the classical adequacy in
energy, protein, essential fats, vitamins and minerals.
Today, it is recognized that foods not only provide
basic nutrition, but can also prevent diseases and
ensure good health and longevity. This concept is not
new to people in some parts of Asia – they have always
believed that certain foods are beneficial to health and
some even therapeutic. But these beliefs were primarily
anecdotal, based on centuries of tradition and largely
lacking scientific bases.
Various terms have been used interchangeably
to designate foods for disease prevention and
health promotion. Designer foods, coined in 1989,
is used to describe foods that naturally contain or
are enriched with nonnutritive, biologically active
chemical components of plants that are effective in
reducing cancer risk (Caragay, 1992). Nutraceuticals was
introduced also in 1989 by the U. S. Foundation for
Innovation in Medicine to refer to “any substance
that is a food or a part of a food and provides
medical or health benefits, including the prevention
and treatment of disease” (DeFelice, 1995). In 1994,
the U. S. Institute of Medicine’s Food and Nutrition
Board defined functional foods as “any food or food
ingredient that may provide a health benefit beyond
the traditional nutrients it contains” (Thomas and
Earl, 1994).
Several factors – scientific advances, consumer
demand, increasing health care costs, an aging
population, technical advances in the food industry,
and changing regulatory environment – have
stimulated the field of functional foods (Hasler,
1996). Scientific investigations have resulted in the
accumulation of scientific evidence supporting the
vital role of diet in overall health and well-being. For
instance, six of the ten leading causes of death in the
United States – cancer, coronary heart disease, stroke,
diabetes, atherosclerosis, and liver disease – have been
increasingly shown to be related to diet.
The Scientific Evidence for Efficacy
A convincing scientific relationship between food
and its health effects can be established by using the
following methods of investigation: epidemiological
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studies, biological and experimental studies, and
intervention trials. No single study design can stand
on its own. Corroborative findings from different
types of studies are needed to form a solid basis for
recommendations designed to improve public health
(World Cancer Research Fund, 1997).
Epidemiology examines the correlation of a
dietary constituent to an outcome, but does not
demonstrate a cause-and-effect relationship. There
are several types: intercountry and intracountry
correlations (ecological), time-trend and migrant
studies, case-control (retrospective) studies, and
cohort (prospective) studies (Clydesdale, 1996; World
Cancer Research Fund, 1997).
Correlation or ecological study is the simplest type of
study for exploring the relationship between a diet and
a disease (e.g. cancer). Carried out at the population
level, it involves comparison of disease incidence rates
with consumption of a food or a food component or
other aspects of the diet. An obvious limitation of
this study is that, while it may suggest a relationship
between a specific environmental factor (e.g. an aspect
of diet) and disease, the actual relationship may be
with a different diet-associated confounding factor.
Moreover, a lack of correlation between an aspect of
diet and disease may disguise an actual relationship,
due to possible varying genetic predisposition in
different populations. Thus, false-positive or falsenegative results may be obtained. Despite these
limitations, correlation studies have special strengths,
particularly when conducted between populations
either internationally or cross-culturally among
contrasting populations within a country.
Migrant studies allow the assessment of whether
the correlations observed in ecological studies are
due to genetic or environmental factors. For example,
populations migrating between areas with different
cancer incidence rates acquire the characteristic of
their new locations for most cancers, often after only
one or two generations. Such findings show that
genetic factors are not primarily responsible for the
large difference in cancer rates in different regions
and countries. Cancers whose incidence shifts with
migration are diseases with environmental causes, and
migrant studies are very important for establishing the
environmental causes of such diseases.
In case-control (retrospective) studies, a group of
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individuals with the disease (case) is compared with a
group without the disease (control) with regard to a
possible risk factor (e.g. diet). Many of the weaknesses
of correlation studies can be avoided in case-control
studies by eliminating known or suspected confounding
factors from the study design or controlling them in
the data analysis. Dietary habits before the onset of the
disease are assessed retrospectively by questionnaire
or interview. Thus, the major drawback of this study
is the heavy dependence on subject recall. Cases and
controls may differ in the accuracy of recalling their
previous diets so that ensuing comparisons may be
biased.
to develop surrogate markers or disease endpoints
that have a predictive value in establishing a causeand-effect relationship with a disease (Clydesdale
1996). Examples of well-accepted markers are
oral leukoplakia in oral cancer, adenomatous colon
polyps in colon cancer, and circulating lipids in heart
disease. Overall, epidemiology backed by convincing
experimental and biological findings can provide
strong causal relationship between diet and disease.
This evidence for a causal relationship is further
strengthened when a biologically plausible mechanism
of action of the constituents of the diet is identified
(World Cancer Research Fund, 1997).
Recall problems and bias are avoided in cohort
(prospective) studies. Dietary information is collected
from a large population, free of the disease at the
beginning of the study, and these individuals are
followed through time, usually for a decade or more,
until a sufficient number of participants develop
the disease. The relationship of the incidence of
the disease to specific characteristics of individual
diets is then analyzed. Cohort studies allow repeated
assessments of diets at regular intervals, examination
of the effects of diet on the disease in question as well
as other diseases, and collection and storage of tissue
samples for subsequent analysis. However, they take
a long time, require a large number of subjects and
are very expensive.
Because of access to body tissues and more
accurate control of laboratory conditions, more
detailed mechanistic information on the action of a
dietary component or food can be derived from animal
rather than human studies. However, these results must
be validated in humans as it is widely acknowledged
that animal models may not physiologically represent
humans.
Certain important associations can be missed in
an epidemiological study if it is not sufficiently large
because of the inadequate statistical power of the
study. To circumvent this problem, the technique of
meta-analysis, which statistically summarizes the results
of a collection of studies, is used. Meta-analysis may
select only prospective studies, or studies judged to
be of high quality. But, unless it includes all relevant
studies from a systematic literature review using fairly
objective criteria for selection, it can repeat or even
magnify the bias of individual studies.
In intervention trials, a control group of individuals
is given an inactive substance, and an intervention
group is given dietary constituents that may affect
disease risk. This study is somewhat similar to trials
used to test drugs. The preferred experimental design
is the randomized controlled trial in which people
are assigned to an intervention or control group
at random. The strength of evidence obtained is
increased if the study is conducted ‘blind’, i.e., the
subjects do not know whether they belong to the
control or intervention group, or ‘double-blind’,
i.e., the investigators do not know either. These
trials usually test the effects of specified levels of
supplementation with dietary constituents (as pills,
capsules or other forms).
Biological and experimental studies can be
carried out on humans or animals or on human, animal
or microbial materials or cell cultures. Unlike most
epidemiological studies, this type of study entails more
than observations - the scientist controls the system
under investigation, makes measured interventions
in different subsets of the study populations and
compares the outcome between those subsets. To
obtain meaningful scientific data, it may be necessary
Likewise, effects observed with in vitro systems
must be interpreted carefully since these systems,
though attractive for their simplicity, may not reflect
the intricacies of the numerous reactions/processes
and interactions that occur simultaneously in the
human body.
Intervention trials are also subject to certain
limitations. The time between the change in the
level of a dietary factor and expected change in the
incidence of the disease is usually uncertain, thus
the trials should be of long duration. Since these
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trials are based on epidemiological studies that have
shown protective effects of a group of foods, there
is always the possibility that the actual active agent or
combination of agents in the foods may not be those
actually employed in the trial. Also, the agents used
may have a protective effect while contained in foods,
but may have unexpected effects in isolation, especially
in doses higher than those found in normal diets.
Bioactive Food Phytochemicals
Plant foods contain many bioactive compounds
in addition to those which are traditionally considered
as nutrients, such as vitamins and minerals. These
physiologically active compounds, referred to simply
as ‘phytochemicals’, are produced via secondary
metabolism in relatively small amounts. Until fairly
recently, they have been generally assumed to be
irrelevant, sometimes even harmful, to human
health.
The number of identified phytochemicals has
increased dramatically in the last decade. Some groups
of phytochemicals which have or appear to have
significant health potentials are: carotenoids, phenolic
compounds (flavonoids, phytoestrogens, phenolic
acids), phytosterols and phytostanols, tocotrienols,
organosulfur compounds (allium compounds and
glucosinolates), and nondigestible carbohydrates
(dietary fiber and prebiotics).
Carotenoids
Among the phytochemicals, carotenoids
have been the most studied. Carotenoids are
tetraterpenoids responsible for the yellow, orange
and red color of many fruits, vegetables, a few roots,
egg yolk, fish like salmon and trout, crustaceans. They
are synthesized by plants, algae, fungi, yeasts and
bacteria, but are merely accumulated from the diet,
unchanged or slightly modified, in some animals.
In foods, about a hundred carotenoids have
been found. Typically a food would have one
to five major carotenoids with a series of minor
carotenoids in trace or very small amounts. The
principal carotenoids encountered in human blood
and are the most investigated in terms of human
health are: β-carotene, α-carotene, β-cryptoxanthin,
lutein and lycopene. These are also the carotenoids
most commonly found in foods (Rodriguez-Amaya,
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1993, 1999).
The provitamin A activity of some carotenoids
(e.g. β-carotene, α-carotene, β-cryptoxanthin) has
been known for a long time. In more recent years,
carotenoids, provitamins A or not, have been
credited with other health-promoting effects:
immunoenhancement and reduction of the risk of
developing degenerative diseases such as cancer,
cardiovascular diseases (CVD), cataract and
macular degeneration (Gaziano and Hennekens,
1993; Krinsky, 1993; Mayne, 1996; Olson, 1999;
Krinsky and Johnson, 2005). These physiological
activities have been attributed to an antioxidant
property, specifically to the ability to quench singlet
oxygen and interact with free radicals (Palozza and
Krinsky, 1992; Palace et al., 1999). However, other
mechanisms of action against chronic diseases
have been increasingly cited: modulation of
carcinogen metabolism, regulation of cell growth,
inhibition of cell proliferation, enhancement of
cell differentiation, stimulation of cell-to-cell gap
junctional communication, retinoid-dependent
signalling and filtering of blue light (Astorg, 1997;
Olson ,1999; Stahl et al., 2002; Krinsky and Johnson,
2005; Stahl and Sies, 2005).
In the 1980s, numerous retrospective and
prospective epidemiological studies in various
countries consistently and strongly showed that
dietary intake of β-carotene or its serum level was
inversely associated with the incidence of cancer,
particularly lung cancer (Ziegler, 1991; Block et
al., 1992; Ziegler et al., 1996). This inverse relation
was also seen with CVD (Gaziano and Hennekens,
1993; Kohlmeier and Hasting, 1995; Mayne, 1996).
β-carotene, however, fell into disrepute when
intervention studies gave the unexpected finding
that this carotenoid given in capsules to smokers
and asbestos workers increased rather than reduced
the incidence of lung cancer (ATBC Study Group,
1994; Omenn et al., 1996).
It was later recognized that β−carotene was
administered alone in the intervention studies at
doses (20-30 mg) much higher than the optimum
daily intake in the epidemiological studies (about 4
mg), in which the diets had other carotenoids and
other food constituents that could act jointly with βcarotene (CARIG, 1996). Moreover, the participants
in the intervention trials were heavy smokers or
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workers exposed to asbestos for a long time; the
oxidative or cancer process might have reached a
stage at which the carotenoid could no longer be
effective. With these considerations, carotenoids
regained their prominence but the current emphasis
is on carotenoids other than β−carotene.
Lycopene’s possible role in the prevention of
cancer has drawn considerable attention (Gerster,
1997; Clinton, 1998; Sies and Stahl, 1998; Giovannucci,
1999; Rao & Agarwal, 1999; Rissanen et al., 2002), with
special emphasis on prostate cancer (Giovannucci et al.,
2002; Hadley et al., 2002; Wertz et al., 2004; StacewiczSapuntzakis and Bowen, 2005). This carotenoid has
also been associated with CVD prevention (Kohlmeier
and Hastings, 1995). A case-control study of 1379
men from 10 European countries (EURAMIC Study)
showed that higher lycopene concentration in body
fat was correlated with a lower risk of heart attack
(Kohlmeier et al., 1997a).
Lutein and zeaxanthin make up the yellow
pigment in the macula of the human retina (Bone
et al., 1988; Handelman et al., 1988) and have
been associated with the reduced risk for macular
degeneration (EDCC, 1993; Seddon et al., 1994), the
principal cause of irreversible blindness in the elderly.
These two carotenoids have also been consistently
linked to the lowering of the risk for cataract (Moeller
et al., 2000).
Although numerous studies support the
protective effect of carotenoids against chronic
diseases, there have been some inconsistencies in
the results, requiring more well-designed studies to
be conducted. The consumption of carotenoid-rich
foods is widely recommended, but caution and more
investigations are recommended to evaluate the
benefits and risks of supplementation (Mayne, 1996;
Granado et al., 2003; Krinsky and Johnson, 2005).
Phenolic compounds
Phenolic compounds comprise one of the most
numerous and widely distributed groups of substances
in the plant kingdom, with more than 8000 phenolic
structures currently known (Bravo, 1998). Natural
phenolics can range from simple molecules, such as
phenolic acids, to highly polymerized compounds,
such as tannins, and their occurrence in foods is
extremely variable.
The most common group of plant phenolics are
the flavonoids, the structures of which are based on
that of flavone, consisting of two benzene rings linked
through a three-carbon γ-pyrone ring. Common classes
of flavonoids include flavones, flavonols, isoflavones,
anthocyanins, catechins (flavanols) and flavanones.
More than 4000 flavonoids have been reported and,
except for catechins (Aherne and O’Brien, 2002), most
flavonoids occur in nature as glycosides.
Flavonoids are found in fruits, vegetables, coffee,
tea and wine. The flavonols quercetin, kaempferol
and myricetin are widely distributed in fruits and
vegetables. Berries, tomato, potato, broad beans,
broccoli, Italian squash, apple, kale and onion are
the richest sources of quercetin (Hertog et al., 1993;
Hollman and Artz, 2000; Aherne and O’Brien, 2002).
Radish, horseradish, endive and kale are relatively high
in kaempferol (Hertog et al., 1993). Naringenin (a
flavanone), rutin (a flavonol glycoside) and tangeretin
(a methylated flavone) are found in citrus fruits.
The health-related properties of phenolic
compounds, particularly flavonoids, are believed to
be based on their antioxidant activity as hydrogen
donating free radical scavengers (Rice-Evans et
al., 1996; Prior and Cao, 2000). The primary target
of radicals are proteins (including enzymes), lipids
(relevant to the induction of heart disease), DNA
(relevant to the induction of cancer) and RNA.
However, the oxidative event that occurs most
frequently inside the body is the oxidation of the
unsaturated fatty acid components of cell membranes
forming lipid peroxides. Many researchers have shown
that lipid peroxides and reactive oxygen species are
involved in the development of a variety of diseases,
including cancer, atherosclerosis, heart disease, kidney
damage, and even accelerated aging (Ames et al., 1993;
Yu, 1996). Flavonoids are also metal chelators and
have been found to bind metals, such as copper and
iron, that catalyze lipid oxidation.
Yang et al. (2001) reviewed the inhibition of
carcinogenesis by dietary polyphenolic compounds
and questioned the link between the antioxidative and
anticarcinogenic properties, asserting that polyphenols
may inhibit carcinogenesis by affecting the molecular
events in the initiation, promotion and progression
stages of cancer. Beyond their antioxidative properties,
flavonoids may act in a variety of ways, such as
deactivating carcinogens, inhibiting the expression
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Phytochemicals and functional foods, Rodriguez et al.
of mutated genes and the activity of enzymes that
promote carcinogenesis, promoting detoxification
of xenobiotics (Kris-Etherton et al., 2002).
Although flavonoids are widely distributed
in plant foods, the isoflavones are found in just a
few botanical families. Although present in several
legumes, soybean is the principal dietary source.
The isoflavones genistein and daidzein and their βglucosides are present at up to 3 mg per g of soybean
(Price and Fenwick, 1985).
Isoflavones, lignans and stilbenes are
phytoestrogens, a group of nonsteroid plant
constituents that elicit estrogen-like biological
response (Murphy and Hendrich, 2002). Lignans
are diphenols associated as minor components
with dietary fiber. Dietary sources of lignans are
oilseeds, cereal grains, vegetables, fruits and legumes.
Flaxseed and sesame seed have been identified as
the richest sources of these compounds (Thompson
et al., 1991; Coulman et al., 2005). Once ingested,
plant lignans are converted by bacteria in the large
intestine into enterolactone and enterodiol, which
are called mammalian lignans because they have been
found only in mammals (Crosby, 2005). Mammalian
lignans are associated with a reduced risk of CVD
and cancer.
Stilbenes are 1,2-diaryl ethenes that are
biosynthesized from cinnamic acid derivatives.
They are widely distributed in liverworts and
higher plants in monomeric, dimeric, trimeric and
polymeric (viniferins) forms (Gorham, 1989). Among
monomeric stilbenes, the major active compound is
trans-resveratrol, and most of the physiological studies
have focused on it (Cassidy et al., 2000). The main
dietary sources of stilbenes are grape and peanut, and
their products. Trans-resveratrol is a phytoallexin that
protects grape vines from fungal infection.
Phytoestrogens can compete with steroid
hormones for various enzymes and receptors and
stimulate production of sex hormone-binding
globulin in the liver. Thus, they may alter steroid
hormone metabolism and may inhibit growth and
proliferation of hormone-dependent cancer. Like
other phenolic compounds, phytoestrogens have
antioxidant activity, and like estrogens, they can
influence lipoprotein metabolism and enhance
vascular reactivity. Phytoestrogens, therefore, have
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potential protective effects against CVD.
Phenolic acids such as caffeic, ferulic and ellagic
acids are widely distributed in fruits, vegetables, tea
and wine; many are present in foods as glycosides.
Ellagic acid is found in high concentrations in
fruits and nuts, specifically raspberry, strawberry,
blackberry, pecan and walnut (Hollman and Venema,
1993).
Phytosterols and phytostanols
Plant sterols or phytosterols are structurally
similar and functionally analogous to the animal
sterol, cholesterol. Phytosterols are triterpenoids
occurring in both free and esterified form. Of
more than 40 phytosterols identified, β-sitosterol,
stigmasterol and campesterol are the most abundant
and are predominantly supplied by vegetable oils
(Piironen et al., 2000; Hicks and Moreau, 2001),
which are rich sources of sterol esters. Ferulic acid
esters of phytosterols, commonly known as oryzanol,
occur in rice bran oil (Kaneko and Tsuchiya, 1954).
Cereals, nuts and vegetables are also sources of
sterols albeit of lesser importance.
A less abundant class of related compounds
are the plant stanols or phytostanols, which
are completely saturated forms of phytosterols.
Phytostanols are derived primarily from corn, wheat,
rye and rice (Hicks and Moreau, 2001). Corn fiber oil,
said to be a unique oil, not only contains fatty acid
and phenolic esters of phytosterols, but also appears
to be the richest source of stanols and stanol esters
(Moreau et al., 1996).
Phytosterols and phytostanols inhibit intestinal
absorption of cholesterol. The cholesterol-lowering
property of these compounds has been established
some decades ago. For instance, β-sitosterol has been
used since the 1950s as a supplement and as a drug
(Cytellin, marketed by Eli Lilly) for lowering serum
cholesterol levels in hypercholesterolemic individuals
(Hicks and Moreau, 2001).
Equally effective in lowering plasma cholesterol,
plant sterol esters, unlike stanols, increase their own
absorption. The resulting increased serum sterol
levels could occasionally approach values seen in
phytosterolemia, a strongly atherogenic hereditary
metabolic abnormality. Thus, plants rich in esterified
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stanols would be preferable in the preparation of
functional foods (Miettinen, 2001).
activity, and lipoxygenase and tumor inhibition (Huang
et al., 1994).
As of September 2000, the US FDA has
allowed a health claim for reducing the risk of
coronary heart disease for foods (spreads and salad
dressings) containing phytosterol and phytostanol
esters (Jones and Raeini-Sarjaz, 2001).
The glucosinolates are sulfur-containing
glucosides prevalent in the cruciferous family of
vegetables, especially the Brassicas (e.g. cabbage,
broccoli, Brussels sprouts, cauliflower), and are also
present at relatively high levels in oilseeds such as
rapeseed and in condiments such as mustard seed.
Over a hundred different glucosinolates have been
identified in the plant kingdom, but only about 10 are
present in cruciferous vegetables (Stoewsand, 1995).
Although the glucosinolates are structurally diverse,
there are only three principal groups, based on the
side-chain structure: aliphatic, aromatic and indolyl
(heteroaromatic) glucosinolates (Mithen et al., 2000).
All the glucosinolates have a β-D-thioglucose group,
a sulphonated oxime moiety and a variable side-chain
derived from methionine, tryptophan, phenylalanine
or some branched-chain amino acids (Fenwick et al.,
1983).
Tocotrienols
Tocotrienols are unsaturated analogs
of tocopherol (vitamin E). They occur in the
unsaponifiable fraction of vegetable oils; rice bran
oil and palm oil are the most significant sources
(Eitenmiller, 1997). A number of plant foods,
ranging from kale and broccoli, to cereal grains and
nuts have also been found to contain tocotrienols
(Piironen et al., 1986).
There are at least four known forms of
tocotrienol, with γ-tocotrienol as the main and
most potent cholesterol-lowering form (Parker
et al., 1993). The cholesterol-lowering effect of
tocotrienols is attributed to their ability to inhibit
hydroxymethylglutaryl-CoA (HMG-CoA) reductase,
the rate-limiting enzyme in the cholesterol synthesis
pathway (Parker et al., 1993). It has been suggested
that α-tocopherol attenuates the inhibitory effect
of γ-tocotrienol (Qureshi et al., 1996). Tocotrienols
have also been demonstrated to possess vitamin E
activity (Tan, 1989), antioxidant activity (Serbinova
et al., 1993) and antitumor properties (Komiyama et
al., 1992). It was hypothesized that the inhibition of
HMG-CoA reductase by tocotrienols also results in
suppression of tumor growth (Elson and Qureshi,
1995).
Organosulfur compounds
Allium compounds are organosulfur
compounds (OSCs) found in Allium vegetables
such as garlic, onion, scallion, chive, shallot and leek,
which account for the distinctive flavor and aroma as
well as the many reported medicinal effects of these
vegetables.
The OSCs in Allium vegetables have been
reported to exert various physiological effects,
including antimicrobial activity, lipid-lowering effect,
hypocholesteremic activity, antithrombic effect,
inhibition of platelet aggregation, hypoglycemic
When the plant tissue is damaged by food
preparation or chewing, the glucosinolates are
brought into contact with and are hydrolyzed by the
endogenous enzyme, myrosinase, to yield a complex
mixture of products mainly isothiocyanates, nitriles
and thiocyanates. Glucosinolate breakdown products
exert a variety of antinutritional and toxic effects in
higher animals, the most thoroughly studied of which
is the goitrogenic effect of some products (Heaney
& Fenwick, 1995). At present there is little or no
epidemiological evidence of this goitrogenic effect
causing a disease in humans.
On the other hand, as summarized by Finley
(2005), in vitro and in vivo studies have reported
that isothiocyanates affect many steps of cancer
development, including modulation of phase I and II
detoxifying enzymes, functioning as a direct or indirect
antioxidant by phase II enzyme induction, modulating
cell signaling, induction of apoptosis (programmed
cell death), control of the cell cycle and reduction
of Helicobacter infections. Apoptosis and modulation
of phase I and phase II detoxification pathways have
been considered the most important mechanisms
by which glucosinolate/isothiocyanates inhibit
carcinogenesis (Mithen et al., 2000; Talalay & Fahey,
2001; Finley, 2005). Glucosinolates are not bioactive
until they have been enzymatically hydrolyzed to the
associated isothiocyanates.
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Nondigestible carbohydrates: Dietary fiber and
prebiotics
There are 3 main types of carbohydrates that
are undigestible in the human small intestines:
nonstarch polyssacharides (NSP), resistant starch
(RS) and nondigestible oligosaccharides (NDOs)
(Voragen, 1998).
Several definitions for dietary fibers have been
suggested. The most widely accepted is a physiological
definition, which considers dietary fibers as vegetable
wall residues that are resistant to enzymatic hydrolysis
in the small intestine. A chemical definition describes
dietary fibers as nonstarch polysaccharides, although
more recently some workers include resistant starch
as a new class. The most commonly used definition
is: dietary fibers are oligosaccharides, polysaccharides
and their hydrophilic derivatives, which cannot
be digested by the human digestive enzymes to
absorbable components in the upper alimentary
tract; this definition includes lignin (Thebaudin et
al., 1997).
NDOs occur naturally in food raw materials
and food products. The most prominent example
are fructans (e.g. inulin), which occur in edible parts
of various plant foods like onion, artichoke, chicory,
leek, garlic, banana, rye, barley and yacon (Voragen,
1998). Galactosyl sucroses (raffinose and stachyose)
are found in soybeans and other leguminous seeds,
while xylooligosaccharides occur in bamboo
shoots. In some foods NDOs are generated during
processing. The NDOs have been described as
prebiotics (Crittenden and Playne, 1996). A prebiotic
is a nondigestible food ingredient that positively
affects the host by selectively stimulating the
growth and/or activity of one or a limited number
of beneficial bacterial species already resident in
the colon (Gibson and Roberfroid, 1995). For this
reason, resistant starches, although considered as
fibers, are not necessarily prebiotics.
Dietary fibers have several recognized
physiological effects: modulation of glucose
absorption, regulation of gastrointestinal transit
time, fecal bulking, acidification of colonic content
and control of cholesterol bioavailability. Prebiotics
on the other hand, selectively modify the colonic
microbiota and modulate hepatic lipogenesis
(Crittenden and Playne, 1996; Roberfroid, 1996).
8
A balanced intestinal flora allows improved bowel
regularity, reduction of bacteria, protection against
a wide range of toxins and increased nutrient
absorption.
Functional Foods from Plant Sources
While the evidence for individual
phytochemicals is not as compelling, overwhelming
evidence from epidemiological studies, biological
and experimental studies, and clinical intervention
trials has demonstrated that a plant-based diet can
reduce the risk of degenerative diseases, especially
cancer and CVD (Block et al., 1992; Ames et
al., 1993; Steinmetz and Potter, 1996; Ness and
Powles, 1997; World Cancer Research Fund, 1997;
Law and Morris, 1998; Kaur and Kapoor, 2001). It
is estimated that plant-based diets prevent 20-50%
of all cases of cancer (Steinmetz and Potter, 1996;
World Cancer Research Fund, 1997). Thus, dietary
recommendations for the prevention of cancer and
other chronic diseases have always emphasized the
consumption of a variety of plant foods. The single
compound approach has given way to the concept
that overall protection against disease is provided by
a range of phytochemicals contained in foods.
Following are plant foods that are established or
emerging functional foods, each one with a body of
scientific evidence on the positive impact on health
that the constituent nutrients and phytochemicals
confer.
Broccoli and other cruciferous vegetables
Cruciferous vegetables contain little fat, are
low in energy, and are sources of micronutrients
(vitamins A, C and E, folic acid, selenium), fiber
and other phytochemicals (carotenoids, coumarins,
flavonoids and other phenolic compounds, and
glucosinolates) (Steinmetz and Potter, 1996; Delaquis
and Mazza, 1998).
A review of 87 case-control studies (Verhoeven
et al., 1996) revealed an inverse association between
consumption of cruciferous vegetables and cancer
risk. This epidemiological evidence is supported
by a host of experimental studies, which have
indicated that glucosinolate breakdown products
exert anticarcinogenic activity in experimental and
animal models (Verhoeven et al., 1997; Hecht, 1999).
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Phytochemicals and functional foods, Rodriguez et al.
Stoewsand (1995) specifically attributed the cancer
chemopreventive effects of Brassica vegetables to two
types of phytochemicals: certain glucosinolates and
S-methyl cysteine sulfoxide.
The indolyl glucosinolate, glucobracissin,
found in high levels especially in Brussels sprouts,
is hydrolyzed by myrosinase to give indole-3carbinol (I3C). This indole is under investigation
for its chemopreventive property, especially toward
the mammary gland. It may reduce cancer risk by
increasing 2-hydroxylation over 16-hydroxylation of
estrogen – this shift in hydroxylation represents a
reduction in estrogenic activity and may be protective
against estrogen-related cancers (Hasler, 1998).
In a human clinical trial, women were given a
massive daily dose of 500 mg I3C (approximately 50
times the estimated average daily intake in the USA)
for one week, resulting in significantly increased 2hydroxylation of estradiol (Michnovicz and Bradlow,
1991). The result suggested that I3C may be a novel
approach for reducing the risk of breast cancer.
However, animal studies have shown that I3C and
other indoles induce both phase I and II enzymes.
Induction of phase I enzymes could activate or
deactivate carcinogens, while induction of phase II
enzymes leads to detoxification. Thus, caution has
been urged before proceeding to extensive clinical
trials (Dashwood, 1998), although similar phase I
clinical trials as the one described above, are ongoing
(Wong et al., 1998).
Three-day-old sprouts of cultivars of certain
crucifers, including broccoli and cauliflower,
contain 10–100 times higher levels of the aliphatic
glucosinolate glucoraphanin than the corresponding
mature plants (Fahey et al., 1997). Glucoraphanin is
hydrolyzed by myrosinase to yield sulforaphane, an
isothiocyanate, which is a phase II enzyme inducer
(Zhang et al., 1992). Hence, broccoli sprouts have
more desirable anticancer properties than the mature
vegetable (Fahey et al., 1997; Nestle, 1998).
Oat
Among the food grains, oat is the most
concentrated source of β-glucan, a soluble nonstarch polysaccharide known to reduce risk of
coronary heart disease (Bell et al., 1999). Various
components such as phytates, phenolics, vitamins
and minerals, which confer other physiological
benefits, are also present.
Oat was the first specific food allowed to have
a health claim under the US Nutrition Labeling and
Education Act (Hasler, 1998). FDA allowed the claim
“soluble fiber from oatmeal, as part of a low saturated
fat, low cholesterol diet, may reduce the risk of heart
disease.” FDA has acknowledged that β−glucan is the
main active ingredient responsible for this health claim
(Oomah and Mazza, 1999).
Several clinical studies starting from 1963
(DeGroot et al., 1963) were conducted to see the effect
of oats on serum lipids. The most conclusive study
was a meta-analysis (Ripsin et al., 1992) summarizing
the oat-product literature on clinical trials of freeliving subjects up to March 1991. Twenty trials were
identified, out of which 12 trials became the bases of
analyses. This report provided the strongest evidence
to FDA that about 3 g per day of soluble fiber from
oat products can achieve a clinically relevant serum
cholesterol-lowering effect, and that the reduction
is greater in individuals with higher initial blood
cholesterol levels.
Four mechanisms have been proposed to explain
the cholesterol-lowering effect of β-glucan from oats
(Bell et al., 1999). First, it has been postulated that
soluble fiber binds to bile acids in the intestinal lumen
resulting in a reduced bile acid pool circulating back to
the liver. This binding action stimulates the production
of more bile acids from cholesterol, thereby reducing
serum cholesterol concentration (Lia et al., 1997). A
second mechanism centers on the short-chain fatty
acids (acetic, propionic and butyric acids) that are
formed from fermentation of soluble fibers in the
large bowel by colonic bacteria (Glore et al., 1994).
These fatty acids are absorbed through the portal
vein, inhibiting the action of HMG-CoA reductase
or increasing catabolism of LDL cholesterol. A third
mechanism involves the delaying of gastric emptying
by oat soluble fiber – this reduces post-prandial serum
insulin concentrations (Inks and Mathews, 1997),
which in turn reduces hepatic cholesterol production
through mediation of HMG-CoA reductase. Lastly,
the increase in intestinal viscosity brought about by
oat soluble fiber may interfere with the absorption of
dietary fat, including cholesterol (Inks and Mathews,
1997).
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9
Phytochemicals and functional foods, Rodriguez et al.
Flaxseed (linseed)
Flaxseed or linseed is a rich source of the
omega 3-fatty acid α-linoleic acid (ALA), viscous
fiber components and mammalian lignan precursors
(Oomah and Mazza, 1999). The high concentrations
of dietary fiber (polysaccharide gum or mucilage),
ALA and lignans have been associated with the many
potential health benefits of flaxseed.
The first meta-analysis examining the relationship
between intake of flaxseed or its components and
risk reduction of disease in humans was presented
by Oomah (2001). Of 24 clinical studies identified,
only 12 (six with flaxseed and six with flaxseed oil),
involving a total of 208 subjects, were found to meet
all the criteria of well-designed clinical trials. Four
of these studies supported the protective effect of
ALA of flaxseed oil against cardiovascular disease.
Three studies concluded that consumption of raw or
defatted flaxseed reduced total and LDL cholesterol.
Five studies in women showed a role of flaxseed in
mediating bone health and its phytoestrogenic and
therapeutic effect in reducing the risk of hormonerelated cancers.
Tomato
Tomato and tomato products have been
the focus of intense investigation in recent years,
especially in relation to prostate cancer (Giovannucci
et al., 2002; Hadley et al., 2002; Campbell et al., 2004;
Stacewicz-Sapuntzakis & Bowen, 2005). Giovannucci
(1999) reviewed the epidemiological literature on the
relationship between intake of tomatoes and tomatobased products and plasma levels of lycopene and
risks of various cancers. Among 72 studies identified,
57 reported inverse associations between tomato
intake or blood lycopene level and the risk of cancer
at defined anatomical sites, and 35 of these inverse
associations were statistically significant. No study
indicated that higher tomato consumption or blood
lycopene level increased the risk of cancer at any of the
sites investigated. Evidence for a benefit was strongest
for cancers of the lung, stomach and prostrate gland.
Data were also suggestive of a benefit for cancers of
the pancreas, colon and rectum, esophagus, oral cavity,
breast and cervix.
Tomatoes and tomato-based products are
the major sources of lycopene in the diet of many
10
countries and lycopene has been considered the
primary phytochemical responsible for the reduction
in the risk of prostate cancer. Tomato, however, is
also a rich source of nutrients such as folate and
vitamins C and E, and of other potentially beneficial
phytochemicals including phenolic acids, phytosterols
and flavonoids (Beecher, 1998). Thus, the possibility
that it is the combination of these compounds
that is responsible for the influence on prostrate
carcinogenesis has been raised (Hadley et al., 2002;
Campbell et al., 2004; Stacewicz-Sapuntzakis &
Bowen, 2005).
Soybean
Soybean has been cultivated and consumed as
food in Asia for over 5000 years. But this ancient
bean was grown abundantly throughout the world
only during the 20th century and scientific interest on
its health benefits started even much later. Soybean
is not only a source of high quality proteins but also
of phytosterols, saponins, phenolic acids, phytic acid
and isoflavones (Messina and Barnes, 1991).
Soybean has been known to have a protective
role in women’s health, particularly the alleviation
of menopausal symptoms and promotion of bone
health. A clinical study of 66 postmenopausal women
found that daily intake of 40 g isolated soy protein
(ISP), containing 90 mg total isoflavones, significantly
increased (approximately 2%) both bone mineral
content and density in the lumbar spine after 6
months (Erdman and Potter, 1997). This finding
suggests that soybeans may have a protective role in
osteoporosis. Asian women have significantly lower
levels of hot flashes and night sweats compared to
western women. A clinical study showed that daily
intake of 60 g ISP for 3 months reduced hot flashes
by 45% in 104 postmenopausal women (Albertazzi et
al., 1998). Considering the significant placebo effect in
these studies, however, use of soybean as substitute
for hormone replacement therapy was considered
premature (Hasler, 1998).
Human ecological observations support a
cancer-protective effect of soybeans. Vegetarians and
population groups (e.g. Japanese women) who often
consume relatively greater amounts of soy products,
have a lower risk of certain cancers, including breast
cancer (World Cancer Research Fund, 1997). Several
classes of anticarcinogenic phytochemicals have
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Phytochemicals and functional foods, Rodriguez et al.
been identified in soybeans, of which the isoflavones
genistein and daidzein are noteworthy because
soybeans are the only significant dietary sources of
these compounds. At present, the epidemiological
data on soy intake and cancer risk are not consistent
(Kris-Etherton et al., 2002). However, a number of
experimental studies have indicated a protective role
of soybeans and its components in cancer.
Population studies show that countries
consuming diets high in soy products have the lowest
rates of CVD. An inverse association between soy
food product consumption and cholesterol level has
been observed in Japanese men and women (Nagata
et al., 1998). A meta-analysis (Anderson et al., 1995) of
38 controlled clinical trials with a total of 730 subjects
showed that daily consumption of 47 g soy protein
resulted in significant decreases in total cholesterol
(9%), LDL cholesterol (13%), and triglycerides (11%)
and an increase in HDL cholesterol (2%).
The most well-documented physiological
effect of soybean is its cholesterol-lowering
effect. Investigations on the specific components
responsible for this effect of soybean have focused
on the isoflavones. In two studies, however, isoflavone
supplements were found not effective in lowering
cholesterol in humans (Nestel et al., 1997; Hodgson et
al., 1998). On the other hand, Crouse and co-workers
(1999) showed that naturally occurring isoflavones
(62 mg) isolated with soy protein reduced the
plasma concentrations of total and LDL cholesterol,
without affecting concentrations of triacilglycerols
or HDL cholesterol, in mildly hypercholesterolemic
individuals. Ethanol-extracted soy protein (with only
3 mg isoflavones) was ineffective.
Animal studies indicate that the cardioprotective
effect of soybeans goes beyond cholesterol-lowering
(Potter, 1998), such as decreases of atherosclerotic
lesion and thrombus formation and in atherosclerotic
plaque. In 1999, the Food and Drug Administration
of the U.S. approved a health claim for soy protein
in reducing the risk of heart disease (Department of
Health and Human Services, 1999).
Citrus
Citrus fruits are principal sources of vitamin
C, folate, fiber, flavonoids and phenolic acids,
monoterpenes, carotenoids and limonoids (Girard and
Mazza, 1998). The various health benefits of citrus
fruits have been attributed to the antioxidant activity
of their constituent flavonoids (flavanones, flavones,
flavonols and anthocyanins) (Benavente-Garcia et
al., 1997). In biological studies, citrus flavonoids
demonstrated anticarcinogenic (antimutagenic and
antiproliferative effects, inhibition of carcinogenic
cell invasion) and cardiovascular (effects on capillary
fragility, platelet aggregation, coronary heart disease)
properties. Citrus flavonoids have also been found
to have antiinflammatory, antiallergic, and antiviral
activities.
The monoterpene D-limonene, which is
the major component of the oil from citrus peel,
has also been shown to protect against cancer; it
induces glutathione transferases, a family of phase
II detoxification enzymes (Crowell, 1997; Gould,
1997). A GRAS (generally regarded as safe) status
has been given to D-limonene as a flavoring agent.
Having no toxicity in humans, D-limonene is a good
candidate for human clinical chemoprevention trial
evaluation. Perillyl alcohol, a metabolite of limonene,
has undergone phase I clinical trials in patients with
advanced malignancies (Ripple et al., 1998).
Citrus fruits are particularly rich in another class
of phytochemicals, the highly oxidized triterpenes
called limonoids. Recent research suggests that these
compounds may have substantial anticancer activity.
However, these studies have been conducted primarily
in in vitro and animal models, requiring further human
studies to confirm such action (Ejaz et al., 2006)
Berries
Berries are not only delicious, low energy food,
but also rich sources of fiber, antioxidant vitamins and
various phenolic compounds (flavonoids and phenolic
acids). The main classes of flavonoids in berries are
anthocyanins, proanthocyanidins, flavonols and
catechins (Wang et al., 1997). Phenolic acids present
in berries are hydroxylated derivatives of benzoic acid
and cinnamic acid (Wang et al., 1997; Torronen, 2000).
Various potential health benefits from berries have been
attributed to flavonoids and phenolic acids.
Berries of Vaccinium sp. have been reported to
possess a wide range of biological activities. Cranberry
and wild blueberry have been shown to prevent
urinary tract infections. This protective effect has been
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11
Phytochemicals and functional foods, Rodriguez et al.
attributed to condensed tannins or proanthocyanidins,
which are said to act as anti-adhesive agents preventing
bacterial colonization (Howell et al., 1998; Ofek et al.,
1996). In wild blueberry, proanthocyanidins have also
been identified as the active agents inhibiting the in
vitro promotion of chemically-induced carcinogenesis
(Bomser et al., 1996).
a cancer chemopreventive effect for tea, which spans
the whole process of carcinogenesis (Dreosti, 1996;
Kuroda and Hara, 1999; Wang et al., 2000). Similarly,
the alleged protection against CVD had also rested
heavily on cellular and animal experiments, carried out
at conditions and/or concentrations unlikely to occur
in man (Tijburg et al., 1997).
Fruit extract of wild bilberry inhibited LDL
oxidation (Laplaud et al., 1997), exhibited astringent
and antiseptic properties, decreased permeability and
fragility of capillaries, inhibited platelet aggregation,
inhibited urinary tract infection, and strengthened
collagen matrices via cross linkages (Morazzoni
and Bombardelli, 1996; Morazzoni and Magistretti,
1990).
A study of green tea drinkers from Japan
(Kono et al., 1992) and another in Norway (probably
mainly black tea drinkers) (Stensvold et al., 1992)
revealed a significant inverse relationship between
tea drinking and plasma cholesterol levels. A similar
but not statistically significant trend was observed in
presumably black tea drinkers from Israel (Green and
Harari, 1992). Additional evidence for a protective
effect of tea against CVD – lowering of blood
pressure and a trend towards reduced coronary heart
disease mortality – was found in the Norwegian study.
These protective effects were also observed in a study
of a population of elderly men in the Netherlands,
although the association was seen with above average
consumption of dietary flavonoids (quercetin,
kaempferol, myricetin, apigenin and luteolin), which
were largely derived from tea (Hertog et al., 1993).
Tea
Tea was first discovered in China, where it has
been consumed for its medicinal properties since 3000
BC (Balentine, 1997). The three main types of tea
are green (unfermented), oolong (semi-fermented)
and black (fully fermented). Green tea contains
significant amounts of catechins, which are easily
extracted from the leaves into hot water infusions.
During the manufacture of black tea, the dimeric
theaflavins and thearubigens are formed by enzymecatalyzed oxidation of catechins. Green tea contains
catechins (90%) and flavonols (10%); black tea has
catechins (30%), flavonols (10%), theaflavins (13%)
and thearubigens (47%) (Tijburg et al., 1997).
Tea has been shown to possess antiviral,
antifungal and antibacterial properties. Evidence has
also suggested that drinking tea provides protection
against cancer and CVD, and it is generally believed
that flavonoids are mainly responsible for these
biological actions. An ecological study of residents
of Shizuoka, Japan, where green tea is produced
and consumed, revealed lower mortality rates from
stomach, lung and liver cancers than comparable
populations in non-green tea consuming areas (Oguni
et al., 1992). Epidemiological studies have shown that
tea may reduce the risk for certain cancers (Blot et al.,
1996; Kohlmeier et al., 1997b). Overall, however, the
epidemiological evidence for a protective effect of tea
against cancer and CVD is still considered inconclusive
(Tijburg et al., 1997; World Cancer Research Fund,
1997; Kris-Etherton et al., 2002). In contrast, research
findings from animal and in vitro studies clearly support
12
Grapes and wine
Grapes and wines contain large amounts of
phenolic compounds including flavonoids (catechins,
epicatechin, quercetin, anthocyanidins), phenolic acids
(hydroxycinnamates) and tannins (Kaur and Kapoor,
2001). The phenolic substances in wine mainly
originate from grapes, but the phenolic profile of
wine is not the same as that of fresh grapes or grape
juice due to significant changes taking place during
wine making.
In certain parts of France, coronary heart disease
mortality is low despite diets high in dairy fat (Renaud
and de Lorgeril, 1992). This phenomenon, referred
to as the ‘French Paradox’ is attributed to high intake
of red wine and has been partly explained by the
association of moderate alcohol consumption with
a decreased risk of CVD. More recent investigations
have focused on the nonalcoholic components,
particularly flavonoids and other phenolics; the
phenolic content of red wine is 20–50 times that
of white wine. Red wine has been shown to inhibit
oxidation of human LDL in vitro (Frankel et al., 1993;
Teissedre et al., 1996), this property being attributed to
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Phytochemicals and functional foods, Rodriguez et al.
wine phenolics. Collectively, as reviewed by Rotondo
and Gaetano (2000) and Wollin and Jones (2001),
phenolic compounds appear to have anti-thrombic
effects as a result of reduced susceptibility of platelet
aggregation, reduced synthesis of prothrombotic and
proinflammatory mediates, decreased expression of
adhesion molecules and tissue factor activity. The
inhibition of platelet-mediated thrombosis was also
observed with grape juice (Freedman et al., 2001).
Aside from its antioxidant activity, resveratrol,
found in grape skin and red wines, induces
quinone reductase, a phase II detoxifying enzyme.
It has antiinflammatory activity and inhibits the
hydroperoxidase activity of cyclooxygenase,
thereby inhibiting the arachidonic pathway that
produces prostaglandins which stimulate tumor cell
growth (Cassidy et al., 2000). In a dose-dependent
manner, resveratrol inhibits the development of
preneoplastic lesions, slowing down the progression
of carcinogenesis (Jang et al., 1997). Other reports
suggest that resveratrol inhibits key enzymes involved
in DNA duplication and synthesis (Fontecave et al.,
1998; Sun et al., 1998). As pointed out by della
Ragione and co-workers (1998), resveratrol seems
a very attractive molecule for the development
of anticancer treatments as well as for inhibiting
lymphocyte proliferation during immunosuppressive
therapies.
Garlic
Garlic is one of the earliest of cultivated
spices and foods and the most widely quoted in the
literature for medicinal properties and health benefits.
A number of epidemiological studies have shown that
garlic consumption is correlated to reduced cancer
risk. An ecological study showed that Shandong
Province, China, an area where garlic consumption
is very high, had the lowest national mortality rate
for stomach cancer (Mei et al., 1982). You et al.
(1989) found that eating more than 1.5 kg/year
of garlic was accompanied by a significantly lower
stomach cancer risk. The Iowa Women’s Health Study
showed a reduced colon cancer risk by almost 50% in
over 40000 women who consumed garlic more than
once a week (Steinmeitz et al., 1994). A review of 20
epidemiological studies by Ernst (1997) suggested
that allium vegetables, including garlic, may confer a
protective effect against cancer of the gastrointestinal
tract. In a more recent meta-analysis, a consistent
inverse association between raw and cooked garlic
consumption and stomach and colorectal cancers
was observed (Fleischauer et al., 2000). In contrast,
garlic supplement consumption in one case-control
study of prostate cancer and in four studies from the
Netherlands, cohort of colorectal, stomach, lung and
breast cancers, did not appear to be associated with
cancer risk.
Components of garlic have been demonstrated
to inhibit carcinogenesis in several experimental
models. These studies have suggested that allyl sulfur
compounds in garlic act primarily on the initiation
phase of carcinogenesis, inhibiting development of
chemically-induced tumors in various sites through
the induction of phase II detoxification enzymes and
inhibition of P 450 E1, the enzyme responsible for
the metabolic activation of carcinogens. The ability of
garlic to inhibit the synthesis of N-nitroso compounds
(Mei et al., 1989) and its antibacterial activity against
Helicobacter pylori, a risk factor in stomach cancer (Sivam
et al., 1997), are two other possible mechanisms.
Studies have indicated that the anticancer properties
associated with garlic are not limited to a particular
tissue and both lipid-soluble and water-soluble allyl
sulfur compounds are effective, supporting the
possibility of multiple mechanisms (Milner, 2006).
Evidence from many experimental studies
shows that garlic protects against CVD by bringing
about lipid normalization, enhanced fibrinolytic
activity, inhibited platelet aggregation and reduced
blood pressure (Petesch and Sumiyoshi, 1999).
These experimental studies are supported by
ecological observations of lowered cardiovascular
incidence in high-garlic consuming populations in
the Mediterrenean region and some places in Asia,
compared to populations who have similar life and
dietary styles (Lin, 1994). Several clinical trials have
been conducted to investigate the cardioprotective
effect of garlic. A clinical study on the effect of garlic
supplementation on the endpoint of cardiovascular
events (myocardial infarction or death) was conducted
in 432 cardiac patients (Bordia and Verma, 1990).
Supplementation reduced the mortality rate by 50%
in the second year and by about 66% in the third year,
and reduced the rate of re-infarction by 30 and 60% in
the second and third year, respectively. A meta-analysis
by Warshafsky and co-workers (1993) summarized the
results of 5 randomized placebo-controlled clinical
trials involving 410 patients. It was shown that an
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13
Phytochemicals and functional foods, Rodriguez et al.
average of 900 mg garlic per day (one-half to one
clove of garlic) could decrease total serum cholesterol
levels by approximately 9%. Another meta-analysis
involving 16 trials reported that 800 mg garlic per
day reduced total cholesterol by 12% (Silagy and Neil,
1994). On the other hand, a multi-center, randomized,
placebo-controlled trial showed that 12 weeks of garlic
intake were ineffective in lowering cholesterol levels
in hypercholesterolemic subjects (Isaacsohn et al.,
1998). The contradictory results in these studies may
be due to methodological shortcomings, differences in
garlic preparation/formulation used (i.e., loss of active
compounds during processing or inhibition of release
of the active components) and insufficient duration of
studies. Rahman and Lowe (2006) analyzed in vitro and
in vivo studies published since 1993, concluding that
although garlic appears to hold promise in reducing
parameters associated with cardiovascular disease,
more in-depth and appropriate studies are required.
Prospect for Developing Countries
In order to materialize the full potential
of phytochemicals/functional foods, a holistic,
concerted, multidisciplinary approach is imperative,
involving workers in diverse fields such as nutrition,
medical sciences, epidemiology, statistics, immunology,
analytical and organic chemistry, biology, biochemistry,
agriculture, food science, food technology and
engineering.
The future of functional foods depends on
the unequivocal demonstration of their efficacy in
promoting health. Epidemiological and intervention
studies, however, require large investigating teams of
researchers from different areas, infrastructure to
cope with large numbers of subjects and substantial
financing to support the different activities for an
extended period. Animal model and cell/tissue
studies are more amenable to conditions in developing
countries, but the results need to be validated in
humans.
A practical approach for developing countries
would be to keep abreast of advances in human health
research in developed countries and concentrate
efforts on the identification of local sources of
phytochemicals for which the scientific evidence is
strong. Accurate quantification of the phytochemicals,
including monitoring and enhancing of their levels
throughout the food chain, and product development
14
for the domestic and international markets could then
be accomplished.
Each country will have to identify and promote
their own sources, as Canada (Oomah and Mazza,
1999), Japan (Namiki, 1994) and China (Dai and Luo,
1996) have already been doing. Many developing
countries have a diversity of yet unstudied or
understudied foods which can have higher levels
of bioactive phytochemicals than those found in
developed countries. The importance of databases on
these compounds cannot be overemphasized. In fact,
reliable data on food composition is a prerequisite to a
successful epidemiological study so that reliable intakes
could be calculated. And a country can forcefully
promote its products only if their compositions
are reliably known. In addition, exploitation of the
beneficial effects of the phytochemicals depends on
how fully we understand their behavior at the different
stages of the food chain.
It is known that the phytochemical composition
can vary markedly as a function of such factors as
cultivar, degree of maturity at harvest, climatic or
geographic effects, soil composition, cultivation
practices, part of the plant utilized. Agronomic and
post-harvest handling and processing measures can
be taken to insure high levels of these compounds
in the diet. Indeed, it is now increasingly recognized
that optimization of the nutrient/phytochemical
contents and profiles of foods, through conventional
plant breeding and agronomic practices or genetic
manipulation, is a viable strategy (Mithen et al., 2000;
Parr and Bolwell, 2000; Schneeman, 2000; van den
Berg et al., 2000; Miettinen, 2001). The possibility
that manipulation of phytochemical metabolism by
expensive molecular techniques may not substantially
improve phytochemical contents beyond what can be
achieved by traditional agricultural procedures (Parr
and Bolwell, 2000) should not be overlooked.
Most of the phytochemicals are prone to
degradation during processing and storage. Thus,
food production must be coupled with optimum food
processing and storage, which can profoundly affect
the health-promoting potential of functional foods.
In fact, as discussed earlier, processing is necessary
to transform some phytochemicals into their active
form. And as shown with carotenoids, food processing
can increase bioavailability by facilitating the release
of the bioactive compounds from the food matrix,
Segurança Alimentar e Nutricional, Campinas, 13(1): 1-22, 2006
Phytochemicals and functional foods, Rodriguez et al.
the first step in the human digestive process (Gartner
et al., 1997; Rock et al., 1998). Thus, processing
conditions should be such that appreciable losses
of the phytochemical are prevented while their
bioavailability is enhanced.
1999; 39:189-202.
Acknowledgment
Block G, Patterson B, Subar A. Fruit, vegetables, and
cancer prevention: A review of the epidemiological
evidence. Nutr Cancer. 1992; 18:1-29.
To CNPq for the visiting research fellowship
granted to the first author and to CNPq and FAPESP
for the financial support of our work in this area
through the PRONEX projects nos. 66.2307/19968 and 2003/10151-4.
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